Resveratrol Preserves Mitochondrial Function By Sirt3 Activation In A Right Ventricle Dysfunction Model

Abstract

<h3>Introduction</h3> Pulmonary Arterial Hypertension (PAH) leads to right ventricular (RV) failure by increasing pulmonary vasculature pressure. Previously we showed that resveratrol (RES) has anti-hypertrophic properties and improved RV function in PAH. However, underlying mechanisms are not fully understood. Of note, sirtuins modulation has been identified as critical mediators that induce cardioprotection. <h3>Objective</h3> To elucidate the contribution of sirtuins in RV protection by RES in a monocrotaline-induced PAH rat model. <h3>Methodology</h3> The Internal Committee for Care and Handling of Laboratory Animals of the Tecnologico de Monterrey approved all animal procedures (protocols 2017-006, 2019-019). Myocyte function and mitochondrial membrane potential (ΔΨm) was characterized by confocal microscopy; mitochondrial respiration was assessed using high-resolution respirometry and calcium retention capacity (CRC) by fluorescence; Western Blot and immunoprecipitation evaluated post-translational modification. Data are presented as percentages, n>3. Statistical significance was set at <i>p</i>< 0.05. PAH is prone to mitochondrial permeability transition pore (mPTP) opening, thus decreasing the mitochondrial membrane potential. The compromised cellular energetics affect cardiomyocyte function by decreasing sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity and delaying myofilament unbinding, disrupting cell relaxation. RES partially protects mitochondrial integrity by deacetylating cyclophilin-D, a critical component of the mPTP, increasing SIRT3 expression and activity and preventing mPTP opening. <h3>Results</h3> PAH is prone to mitochondrial permeability transition pore (mPTP) opening by decrease 81% CRC, thus reducing the mitochondrial membrane potential by 47%. The compromised cellular energetics showed by 26% decrease in mitochondrial oxidative phosphorylation affect cardiomyocyte function by decreasing shortening and less efficient with slower time to peak shortening (TTPS, 81%) and half relaxation (TTHR, 41%). RES partially protects mitochondrial integrity by decreasing 51% cyclophilin-D hiperacetylation, a critical component of the mPTP, and increasing 3.5 fold SIRT3 expression thus preventing mPTP opening. <h3>Conclusion</h3> Preventing CypD hyperacetylation through SIRT3 partially contributes to preserving mitochondrial function, which holds an energetic cellular capability to maintain myocyte function. These findings provide new insight into the mechanisms underlying RES protection.